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CN101631600B - Packing system and method for chromatography columns - Google Patents

Packing system and method for chromatography columns Download PDF

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Publication number
CN101631600B
CN101631600B CN2008800076959A CN200880007695A CN101631600B CN 101631600 B CN101631600 B CN 101631600B CN 2008800076959 A CN2008800076959 A CN 2008800076959A CN 200880007695 A CN200880007695 A CN 200880007695A CN 101631600 B CN101631600 B CN 101631600B
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chromatographic column
bed
terminal units
bed body
filter
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CN101631600A (en
Inventor
K·格鲍尔
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Cytiva Bioprocess R&D AB
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GE Healthcare Bio Sciences AB
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/20—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the conditioning of the sorbent material
    • B01D15/206—Packing or coating
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/50—Conditioning of the sorbent material or stationary liquid
    • G01N30/56—Packing methods or coating methods
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6052—Construction of the column body
    • G01N30/606—Construction of the column body with fluid access or exit ports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/22—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the construction of the column
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/50—Conditioning of the sorbent material or stationary liquid
    • G01N30/56—Packing methods or coating methods
    • G01N2030/562—Packing methods or coating methods packing
    • G01N2030/565—Packing methods or coating methods packing slurry packing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6004—Construction of the column end pieces
    • G01N30/6021—Adjustable pistons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6004—Construction of the column end pieces
    • G01N30/603—Construction of the column end pieces retaining the stationary phase, e.g. Frits

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)

Abstract

The invention relates to a system for packing chromatography columns with a chromatography medium and packing method for use in such columns. In particular, the invention relates to a method and system for packing chromatography columns which utilises an external drive means to compress a bed of particulate medium to a target bed height.

Description

The loading system and the method that are used for chromatographic column
Technical field
The present invention relates to a kind of packing method be used to utilizing chromatographic media to load the system of chromatographic column and be used in such chromatographic column, using.More specifically, the present invention relates to for improvement of the loading system and the method that chromatographic media are loaded in the chromatographic column.
Background technology
The chromatographic column of using in liquid chromatogram generally includes the tubular body that is packaged with the porous chromatographic media, and carrier fluid flows through from the porous chromatographic media, collects by the material between carrier fluid and the porous media solid phase and separates.Before any separation process, the preparation of bed body must be from must being introduced into the pulp particle in the chromatographic column.The correct filling that bed body forming process is called as " filling process " and bed body is the key factor that impact comprises the column performance of packed bed.The purpose of filling process provides the bed body with optimal compression amount-optimal compression coefficient compression.
Particularly, porous media is to form by the discrete particle suspension that curing is called as " slurry ", and slurry usually is pumped or injects or suck in the chromatographic column from an end.Usually by make slurry flow to particle hold back filter and further the filter cake that forms of compression so that it is loaded into realizes slurry curing in certain volume in packed bed, if this volume is less than filter cake only sedimentation and volume that the sedimentation bed that forms will occupy under the impact of gravity.The degree of compression depends on the type of chromatographic media and the common range between 2-20%.The efficient of chromatographic isolation subsequently depends on liquid distribution and the gathering system in liquid inlet and the exit of packed bed, but mainly is uniformity and the stability that depends on the packed bed of formation.If packed bed is inhomogeneous and unstable, for the chromatographic isolation of carrying out at the bed body, will be subject to bad impact so.The uniformity of packed bed and stability depend on the optimal compression degree, must determine the optimal compression degree for each column size (width or diameter), bed height and the experiment of bed body medium.
It is known (for example referring to US2003/0146159) that several methods for the filling chromatographic column are arranged in the prior art." flow filling " is a kind of method that chromatographic column (namely the chromatogram column diameter is approximately the chromatographic column of 1-10mm) and half preparative chromatography post (namely the chromatogram column diameter is the chromatographic column of 10-100mm) or larger chromatographic column are analyzed in preparation that is normally used for.When flowing filling, by the end sealing with chromatographic column of sieve plate or filter.At the other end, the suspension of slurry or filling material is pumped or injects in the gc column tube.Filter bed forms and increases gradually against sieve plate, until form filter cake.Subsequently by with the filling solvent that is higher than the flow velocity diafiltration of using flow velocity in the operation a plurality of (approximately 3-10) chromatographic column volume the bed body further being compressed to its " target bed height ".Carry out under curing and the effect that is compressed in penetration subsequently, penetration is that a body keeps diafiltration by the reaction of the required barometric gradient of liquid flowing speed of a body to being used for.In case the bed body is by by after the compression of flowing, flowing just is stopped, and closes the outlet that is positioned at the chromatographic column bottom and adapter or upper end unit is adjusted to the object height of compressed bed.Relaxing when this adjusting is finished to avoid compressed bed to surpass target bed height fast.
The shortcoming that mobile packing method has is that the filling material bed body that compresses in this way is axially inhomogeneous, produces maximum compression during the compression step that flows and then produce zero compression at the top of packed bed near the outlet of chromatographic column.This is just so that in case filling is flowed and is stopped and upper end unit is brought to the position, will cause the serious lax of a body and particle re-arrangement may occur.According to the type of medium and the geometry of packed bed, the intrinsic gradient in bed body compression of this method may cause a body poor stability and column efficiency low.
The heavy caliber chromatographic column that the standard method of mobile filling may and not be suitable for using in preparative chromatography.Inter alia, the equipment of designing need to apply certain filling flow velocity and therefore make filling pressure often is nonconforming apparently higher than operating subsequently required pressure.In order to revise this problem, used the packing method that depends on the mechanical type axial compression.Axial compression methods moves axially to realize the compression of a bed body by adapter (terminal units).Therefore, during loading, the demand of liquid high pressure in the chromatogram column space is eliminated.Another advantage of Axial compression methods is that a body is in axial direction evenly compressed, and this is with regard to the problem of the lax and particle re-arrangement having been avoided occurring in the mobile packing method.
Because gradient and bed body space in the body compression all can appear in wall section friction effect, above-mentioned two kinds of methods.Radially the geometry of a body is depended in the impact of inhomogeneities, namely the ratio of diameter and height.As mentioned above, in axial direction compression gradient and a bed body voidage has significantly difference between mobile packing method and Axial compression methods.
A shortcoming of axial compression is to make the chromatographic column of in this way filling need to be used for the device of mobile terminal unit and be used for this device that moves of control.Being used for this typical method that moves is motor-driven or hydraulic system.Because these devices are connected to chromatographic column or are structured in the chromatographic column, so the cost of axial compression chromatographic column and mechanical complexity will be apparently higher than the filling chromatographic columns that flows.
Before carrying out any curing and compression, medium must be introduced in the chromatographic column.Preferably enter through center slurry nozzle or valve and prepare the heavy caliber chromatographic column in the chromatographic column by spraying slurry.So just realized that a kind of is preferred closed system method for hygienic reason.Can be designed to use movably adapter to carry out the axial compression filling or use the filling of flowing of fixing terminal units based on the chromatographic column of pulp stock valve design.
Definition
" analyte " should be defined as the natural or synthetic material that obtains, compound or chemicals, or its product or derivative or metabolin.For fear of doubt, this term should comprise for example for example medicine and/or pro-drug of protein, peptide, amino acid and nucleic acid and synthetic molecules of biomolecule.
" medium " should be defined as can realizing therein any material of chromatographic isolation.The example of medium includes but not limited to realize that ion-exchange chromatography separates, size exclusion chromatograph separates, affine material in conjunction with chromatographic isolation and reversed phase chromatography separation.
" disposable " chromatographic column is characterised in that the pretreated chromatographic media for the work that reduces installation and confirm/verify, otherwise then needs to carry out these work in the non-once chromatographic column.Minimally, preliminary treatment comprise that the bed body of porous media is shaped.Other preliminary treatment can be to reduce microbial load, sterilization, depyrogenation etc.
Disposable chromatographic column can be used as the single-use chromatographic column, that is to say that the user need not carry out cleaning, and cleaning requires before reusing packed bed to be confirmed (such as test, checking etc.).
An embodiment of disposable chromatographic column is the complete chromatographic column that provides with the prefill chromatographic media.
Another embodiment of disposable chromatographic column is made of the first equipment and the second equipment, the first equipment representational framework or conduit, be designed for and bear one or more sides upward pressure and the load that operating period is added in packed bed, purpose is in order to provide spatial stability to packed bed, the second equipment represents to hold the container, sleeve pipe, sleeve, pocket of porous media or bed body etc., and it is connected to the first equipment and is used for operating.For a rear embodiment, porous media is accommodated in the second container and can changes when framework is reusable.In the case, be used for operating the required porous media degree of compression and can in the medium that will be received inserts framework, regulate (referring to for example US2002/0166816 and WO2005/009585) afterwards.
" do not become one with chromatographic column and be connected to the drive unit of chromatographic column from the outside " refers to that drive unit is independent community, only uses when the filling chromatographic column and removed when the operation chromatographic column or separate with chromatographic column.Therefore, when the terminal use operated chromatographic column, drive unit did not exist and is not connected to chromatographic column yet.
Summary of the invention
Target of the present invention provides a kind of packing method that has overcome the various shortcomings of method of the prior art.
Major advantage of the present invention is to prepare packed bed by Axial compression methods, the advantage that produces is improved bed body stability and chromatographic column efficient, and does not need the high mechanical complexity in the conventional desired chromatographic column structure of axial compression chromatographic column solution.This just allows to reduce significantly cost.
Another advantage of the inventive method is that it also is suitable for low pressure liquid Transporting equipment (for example peristaltic pump), reason be to compress mainly by external driver device for example compression frame realize, rather than by the required high pressure of compression that flows.
Another advantage of the inventive method is that the filling/filling of chromatographic column can be carried out as a closed system, that is to say chromatographic column even can fill/load under the aseptic condition that begins from pre-sterilized chromatographic column and pre-sterilized chromatographic media.Therefore the method can be used " can process at any time " or the chromatographic column of " disposable ".
And further advantage is that chromatographic column is scalable (namely increases or the size that reduces chromatographic column to obtain predictable performance).This is the reason of finishing before the axial compression step at the adapter position place that raises owing to being by the slurry nozzle chromatography column.This just allows slurry to distribute with comparing based on a kind of mobile filling (for example referring to US6524484) with use nozzle of fixation ends Unit Design more equably on the cross section of chromatographic column.For the latter, filling must be carried out under constant bed height and target bed height, and this may cause respectively the gradient of packed bed density and compression.
It is isometric that another advantage of the inventive method is that chromatographic column does not need with axial compression chromatographic column of the prior art, and reason is need to before the bed body begins to be shaped all slurries all not introduced in the chromatographic column.
A further advantage of the invention is and compare required adapter (terminal units) stroke minimum also with the system that uses known method so allow more compact structure.
Use according to the first of the present invention, a kind of method for load the axial-flow type chromatographic column with the bed of particulate medium body of target bed height be provided,
Described chromatographic column comprises:
The housing that comprises long and narrow tubular sidewall;
By relative, axially spaced the first terminal units and the second terminal units that described sidewall separates, wherein at least one described unit can move axially with respect to another described unit by drive unit;
Near the first filter of described first module with near the second filter of described second unit, they define be used to the sealing bed body space that holds the bed of particulate medium body with sidewall and wherein the first filter and/or relatively moving of the second filter can change a height;
Described the first terminal units comprises be used to the first valve gear that utilizes described granule medium packed bed body space; And be used for adding liquid or from the bed body space, removing the first port of liquid to the bed body space;
The second terminal units comprises for adding liquid to the bed body space or remove the second port of liquid from the bed body space;
Described method comprises:
I. the axial spacing between described the first filter and the second filter is adjusted to the distance greater than target bed height;
Ii. the suspension of granule medium is introduced in the bed body space so that the bed body of granule medium to be provided therein by the first valve gear;
Iii. the bed body that moves axially the compressing grains medium by the first terminal filter and/or the second terminal filter is to form target bed height;
It is characterized in that by not becoming one with chromatographic column and being connected to the described drive unit performing step iii of chromatographic column from the outside).
Use according to the second of the present invention, a kind of system for load the axial-flow type chromatographic column with the bed of particulate medium body of target bed height is provided, described system comprises:
I. chromatographic column comprises:
The housing that comprises long and narrow tubular sidewall;
By relative, axially spaced the first terminal units and the second terminal units that described sidewall separates, wherein at least one described unit can move axially with respect to another described unit by drive unit;
Near the first filter of described the first terminal units with near the second filter of described the second terminal units, they define be used to the sealing bed body space that holds the bed of particulate medium body with sidewall and wherein the first filter and/or relatively moving of the second filter can change a height;
The first terminal units comprises be used to the first valve gear that utilizes described granule medium packed bed body space; And be used for adding liquid or from the bed body space, removing the first port of liquid to the bed body space;
The second terminal units comprises for adding liquid to the bed body space or remove the second port of liquid from the bed body space;
Ii. drive unit;
It is characterized in that described drive unit does not become one with chromatographic column and is connected to chromatographic column from the outside.
Description of drawings
Fig. 1 is the schematic cross-sectional view of chromatographic column in the prior art, shows its essential characteristic.
Fig. 2 shows the schematic three dimensional views of the viewgraph of cross-section that can use the chromatographic column that the method according to this invention loads.
Fig. 3 shows the schematic three dimensional views of the viewgraph of cross-section that can use another chromatographic column embodiment that the method according to this invention loads.
Fig. 4 is the schematic three dimensional views of using the chromatographic column of the method according to this invention filling.
Fig. 5 is the schematic diagram for the system that uses the method according to this invention filling axial-flow type chromatographic column.
Fig. 6 shows on the chromatographic column of the filling according to the present invention with the chromatogram of upper reaches (dotted line) and dirty (solid line) pattern chromatographic separation of acetone.
Fig. 7 has introduced a kind of for calculating the plate height of reduction and the method for dissymmetry factor according to the elution crest.
The specific embodiment
Fig. 1 schematically shows the critical piece of known chromatographic column 1 in the prior art (for example referring to US6524484).Chromatographic column has the sidewall 11 that columniform liquid can't permeate, and maybe can be that transparent high strength/enhancement mode polymeric material is made by stainless steel for example.The top of sidewall 11 openings and bottom are closed by top and bottom end assemblies or unit 12,13.Each terminal units has end plate 3 that the liquid of sealing assembling can't permeate blocking the opening of sidewall 11, and preferably by stainless steel or high-strength engineering plastic material for example polypropylene make.End plate is fixing and radially extend beyond sidewall and support as holding flange 22 by metallic plate 2 being relied on its outer surface, passes holding flange 22 adjustable pull bar 14 is housed.These parts connect tops and bottom end assemblies 12,13 and help this structure to bear high hydraulic pressure.
The opening 31 that each end plate 13 has a through be used for inner in chromatographic column and the packed bed body space 9 that defined by sidewall 11 and connector assembly 12,13 between be communicated with.Path by opening 31 is subdivided into pipeline separately, is connected with outside by connecting manifold 8.
Filter course 4 is made by filtration or woven plastics or steel usually, extends the area that covers bed body space 9 at the inner surface of end plate 3.The inner surface 35 of end plate 3 is indent after filter course 4, for example is as shown in the figure cone, and preferably utilizes the ribs (not shown) to support filter course 4 from the rear, distributes passage 34 to define between them.Connecting pipeline wherein, namely the mobile phase pipeline 33, inwardly openly distribute in passage 34 to this, and outside open mobile phase connector 81 to manifold 8.
The centre bore 41 that inlet valve equipment 5 extends internally and passes end plate opening 31 and pass through hermetically filter course 4 from manifold 8.One or more pipeline of inlet valve 5 control manifolds 8 directly is communicated with bed body space 9, namely walks around filter course 4.Shown here is by valve 5 controls, and passes through connector 82 and the outside first and second valve keyholed back plate roads 51,61 that are connected of manifold 8.
The packed bed of particle stationary phase material is filled the bed body space 9 between filter course top and the bottom.Packed bed can by above-mentioned " filling of flowing " method form simultaneously fixing by inlet valve 5 with the form of slurry preferably in the upper part of chromatographic column is introduced into a body space.Too much liquid flow by bed body, filter course 4, distribute passage 34, pipeline 33 and be removed (arrow B) by connector 81.Be retained by filter course 4 owing to fixing, therefore the bed body is constantly grown up during whole process all the time.Carry out (namely the bed body is to being used for keeping diafiltration to pass through the reaction of the required barometric gradient of liquid flowing speed of bed body) under curing and the effect that is compressed in penetration subsequently.Compress significantly the bed body of growth by introduce slurry with very high flow velocity.Fill flow velocity by optimizing, just can realize the expectation compressed coefficient for packed bed.In case the bed body just stops pulp flow and closes inlet valve 5 by by flowing compression and with fixedly being added in the chromatographic column of requirement.The method does not need upper head plate 3 is carried out any adjusting so that end plate is in fixing bed height (target bed height) all the time in whole process.
A kind of optional method that is used for compression stationary phase bed body is to carry out mechanical axial compression by moving axially of adapter or end plate 3.This can utilize the motor-driven or the hydraulic system that are connected to chromatographic column or are structured in the chromatographic column to realize (not shown in figure 1).
After chromatographic column filling valve device 5 is closed, move and sent into (arrow " A ") by the mobile device 81 that is connected, enter the distribution passage 34 interior filter courses 4 that also pass through with by the downward elution of packed bed through pipeline 33, realize the separation of its component or analyte.The liquid phase eluant moves device 81 outflows (arrow " B ") that are connected for collecting where necessary by the filter course 4 of bottom end assemblies 13 and by it.Although this is the example of " downflow system " chromatogram, realize chromatographic isolation by moving down by chromatographic column of mobile phase therein, but it should be understood by one skilled in the art that separation also can pass through alternatively " up flow type " chromatogram and realize, as long as move by chromatographic column and reverse thus flow direction by pumping upwards simply.Under this pattern, move and will locate to enter chromatographic column at connector 81 (arrow " B ") mutually, move up by mutually fixing or granule medium, and collect from connector 81 (arrow " A ") at the chromatographic column top.
Fig. 1 and above explanation are for the main relation of introducing each several part and typical operator scheme.It should be understood by one skilled in the art that and the following description content in what also will embody to some extent is that other concrete structure and operator scheme goes for different types of process.
Fig. 2 shows the viewgraph of cross-section according to chromatographic column of the present invention.Chromatographic column 101 comprises tubular shell 111, the first terminal units 112 (part illustrates) and the second terminal units 113, is fixed together to form the fluid tight envelope by O type ring 107/108 and the pull bar 114 with head 116.The first filter 104 and the second filter 106 are respectively near the first terminal units 112 and the second terminal units 113.These filters 104,106 define be used to the bed body space 109 that holds the bed of particulate medium body with sidewall 111.
Housing 111 and terminal units 112,113 usually by stainless steel or high strength plastic materials for example polypropylene consist of.In a preferred embodiment, when chromatographic column is used to the isolating biologically active material, material be biologically inert so that it can not cause immune response in the human body according to American Pharmacopeia (USP) VI class.Pull bar 114 with head 116 is fixed to housing 111 to form the liquid-tight bed body space 109 that can bear high operating pressure with terminal units 112,113.
Filter 104,106 all be arranged on terminal units 112,113 inner surface and be used for (with sidewall 111 together) define a body space 109 and be used for preventing that granule medium from leaking from bed body space 109.Terminal units 112 and 113 (and the first filter 104 and second filter 106 of therefore being attached thereto) relative to each other can move axially.In Fig. 2, terminal units 112 can move axially with respect to the second terminal units 113 in housing 111, but should be appreciated that in other embodiment it all is possible that one of terminal units or both (and therefore filter 104,106) relative to each other can move axially.
Height by at first regulating the first terminal units 112 so that the distance between the first filter 104 and the second filter 106 come to load a body space 109 with the bed of particulate medium body greater than target bed height.Under this state, pull bar 114 and head 116 are not connected to chromatographic column.The distance of terminal units fixes by external drive or compression frame (not shown).By valve gear 120 suspension of slurry or granule medium is introduced in the chromatographic column subsequently, valve gear comprises centre bore 121 and nozzle 124.When suspension being added in the bed body space 109, too much liquid also can be removed to form by port one 40 settled bed of granule medium from bed body space 109.After the fixedly phase of introducing aequum, with regard to shut-off valve assembly 120 and nozzle 124.Subsequently by the terminal units 112 that realized by external drive or compression frame (not shown) and filter 104 move axially compress settled bed to reach target bed height.Can not be manually controlled or control by software mode the target bed height that reaches required with the become one external drive of part of chromatographic column structure.Terminal units subsequently respectively the help by pull bar (114) and head (116) relied on fixed to one anotherly, and subsequently chromatographic column is discharged from external drive or compression frame.
In Fig. 2, nozzle 124 is shown as and is in it towards the filling position of bed body space 109, but should be appreciated that it also can be withdrawn into closed position in top end plate 112 after having filled chromatographic column.Nozzle 124 and valve gear 120 are locked in by the locking device (not shown) and open or close the position.Can use large-scale nozzle to help in the bed body space, to distribute and load fifty-fifty slurry.Be used for respectively realizing at filler valve and nozzle place that a kind of optional mode of opening/closing function is nozzle to be fixed in the body space (and therefore and not recoverable) and to be arranged near the displaceable element or sleeve pipe according to its position open and/or closed nozzle in nozzle inboard or the outside.
Comprise one or more mutually mobile or liquid for the analyte that separates in chromatographic column or material and passed through 133 addings of the first port.Liquid enters in the bed body space 109 that is filled with as mentioned above granule medium through the first filter 104 subsequently.The chromatographic isolation that is directed in this way the analyte on the granule medium be by mobile phase introducing with by carrying out mutually elution and realize mobile.Mobile mutually the most at last through the second filter 106 and by 40 discharges of the second port one.Just can collect subsequently the resulting mobile phase cut that comprises different analytes.
It should be understood by one skilled in the art that chromatographic column can be as mentioned above with the operation of " dirty " pattern or with the operation of " upper reaches " pattern, this moment mobile phase flow direction opposite so that its move up along chromatographic column.In upflow mode, move and will enter chromatographic column by the second port one 40 mutually, in bed body space 109, upwards move through the bed body of granule medium, leave chromatographic column at the first port 133 places and be used for collecting.
Fig. 3 is the viewgraph of cross-section according to chromatographic column of the present invention.Chromatographic column is similar to the chromatographic column among Fig. 2, and wherein a lot of features are all identical with the feature introduced among Fig. 2.Therefore chromatographic column have for the granule medium suspension is added in the bed body space 209 valve gear 220 be used for adding or collecting mobile the first port 233 mutually.But, the place that chromatographic column is different from previous embodiment is that it has the second port 240, comprise that extending through the second terminal units 213 arrives also (by hollow component 260) and the passage 242 that bed body space 209 fluids are communicated with, and can add or collect liquid thus.Can obviously find out from figure, the second port 240 is in and the first port 233 essentially identical levels or height, therefore help to/from chromatographic column add with collect mutually mobile.The further advantage that this set has is the installation that it helps chromatographic column, has reduced the risk of siphon and has reduced the possibility in the air intake chromatographic column.
The setting of all parts is similar to the mode of introducing among Fig. 2.Chromatographic column 201 comprises tubular shell 211, the first terminal units 212 (part illustrates) and the second terminal units 213, is fixed together to form the fluid tight envelope by O type ring 207/208 and the pull bar 214 with head 216.The first filter 204 and the second filter 206 are respectively near the first terminal units 212 and the second terminal units 213.These filters 204,206 define be used to the bed body space 209 that holds the bed of particulate medium body with sidewall 211.The first terminal units 212 and the second terminal units 213 can by the external drive (not shown) for example can be manually or under software control actuator, forcing press or the framework of automatic operation relative to each other move axially.Filter 204,206 also can relative to each other move axially with terminal units near the first terminal units 212 and the second terminal units 213.In illustrated embodiment, only have terminal units 212 and the first filter 204 to move axially with respect to the second terminal units 213 and filter 212, but should be appreciated that in other embodiment it all is possible that one of terminal units and filter or both relative to each other can move axially.
As shown in Figure 2ly with the bed of particulate medium body chromatographic column is filled to target bed height.Utilize the external drive (not shown) regulate the first terminal units 212 height so that the distance between the first filter 204 and the second filter 206 greater than target bed height.By valve gear 220 suspension of slurry or granule medium is introduced in the chromatographic column subsequently, valve gear comprises centre bore 221 and nozzle 224.Too much liquid can be removed to form by passage 242 and port 240 settled bed of granule medium from bed body space 209.Subsequently by the terminal units 212 that realized by the external drive (not shown) and filter 204 move axially compress settled bed to reach target bed height.External drive can be manually controlled or control by software mode the target bed height that reaches required.Terminal units is relied on fixed to one another by the help of pull bar (214) and head (216) respectively subsequently.
Comprise one or more mutually mobile or liquid for the analyte that separates in chromatographic column or material and passed through 233 addings of the first port.Liquid enters in the bed body space 209 that is filled with as mentioned above granule medium through filter 204 subsequently.The chromatographic isolation that is directed in this way the analyte on the granule medium be by mobile phase introducing with by carrying out mutually elution and realize mobile.Move mutually and will arrive the second ports 240 and finally leave chromatographic column through the second filter 206 and by passage 242.Just can collect subsequently the resulting mobile phase cut that comprises different analytes.
It should be understood by one skilled in the art that chromatographic column can be as mentioned above with the operation of " dirty " pattern or with the operation of " upper reaches " pattern, this moment mobile phase flow direction opposite so that its move up along chromatographic column.In upflow mode, mobile will enter chromatographic column by the second port 240 mutually, move and upwards by the bed of particulate medium body in the bed body space 109, leave chromatographic column at the first port 233 places and be used for collecting along passage 242.
In illustrated embodiment, hollow component 260 is integral parts of chromatographic column.But, should be appreciated that hollow component 260 does not just need to be integrated in the chromatographic column by utilizing the connector made by suitable material (such as polypropylene, polyurethane etc.) and suitable pipeline.
Add and collect the mobile use of having simplified mutually aspect operating personnel process and control at the equal height of single terminal units, reduced air and entered the risk of system and reduced to be used for setting up the required space of chromatographic column.
Fig. 4 shows the larger schematic three dimensional views of the column diameter of chromatographic column among Fig. 3, and the surface of chromatographic column is more obvious thus.Chromatographic column is included in transportable the first terminal units 317 during the compression step, the second terminal units 318 and housing 311, by pull bar 314 and head 316 they is fixed together to form the fluid tight envelope.The granule medium of slurry form can be introduced in the body space (not shown) by valve gear 320.The first port 333 is as the mutually mobile or liquid line that comprises the analyte that will separate at granule medium.End in the second port 340 with the hollow component 360 that bed body space fluid is communicated with by the outlet (not shown) in the chromatographic column bottom, can collect thus the suitable cut of the mobile phase that elution goes out from chromatographic column.Can find out as shown in the figure, the second port 340 is in and the first port 333 essentially identical levels or height, can introduce thus (or collection) mobile phase.This set helps user's operation and sampling.In the embodiment shown in fig. 4, the capacity of chromatographic column is approximately 10 liters.Should be appreciated that more the column capacities of wide region also is possible, usually in from 0.1 to 2000 liter scope.Preferred capacity when chromatographic column is used as disposable chromatographic column is in 0.5 to 50 liter scope.
Fig. 5 is the schematic diagram for the system that uses the method according to this invention filling axial-flow type chromatographic column.This system comprises the chromatographic column 401 of as above introducing in Fig. 2.Chromatographic column is connected to external driver device 470 (for example compression frame), its utilize platform 472 and 474 can regulate can axially movable the first terminal units (not shown) and the first filter (404) in the bed body space 409 of chromatographic column with respect to the height of the second terminal units (not shown) and the second filter 406.
At first by pump 485 filling liquid from container 480, pump 485 is communicated with to help from chromatographic column with outlet valve 450 fluids or removes air at least from bottom distribution system and filter course in system.Too much liquid or air can be by chromatographic column 401 upper entrance/outlet port from chromatographic column, remove with as waste material 460 discharges.Pressure sensor 490 the startup stage and/or subsequently filling stage during pressure in the monitoring chromatographic column.
The first terminal units and filter 404 at first are adjusted to position H 0(be shown in the drawings 474 0) so that the distance between the first filter 404 and the second filter 406 greater than the target bed height in the bed body space 409.Slurry in the container 430 or the granule medium of suspension form are introduced in the column bed space 409 by inlet valve 420 under pressure by pump 435 subsequently.Container 430 interior remaining any residual slurry can be by being washed in the body space 409 by the loaded with liquid clean container 430 of valve 433 usefulness from container 431.When slurry being introduced in the bed body space 409, too much liquid also can remove to form the settled bed of granule medium in the bed body space by exporting 440.Too much liquid flows out and scraps as waste material 460 through outlet valve 450.During curing schedule, also can control to realize to packed bed precommpression in various degree by the flow velocity of regulating pump 435 by the pressure in the sensor 490 monitoring column bed space 409.
At last, by platform 474 is reduced to position H F(be shown in the drawings 474 F) cause the first filter 404 to move axially and realize the bed body is compressed to its target bed height with respect to the second filter 406.According to the type of chromatographic media, can load by flowing and will load process control by the final compression of axial compression and arrive different precommpression degree.Upper end unit is reduced to final position H FAfterwards, utilize pull bar stationary chromatographic post terminal units, then chromatographic column can be discharged from compression frame.
Fig. 5 and above explanation are in order to introduce the method for filling chromatographic column.Other settings that it should be understood by one skilled in the art that pump, container and sensor also are possible.When filling should be satisfied the disposable chromatographic column that the control level of microbial load is required or the chromatographic column that should produce under aseptic condition, use disposable liquid conveying equipment for example to expect that bag and pipeline are preferred.
Fig. 6 shows chromatographic isolation efficient by the example of the spike pulse test realized in 10 liters of chromatographic columns according to the present invention, with dirty (solid line) and the operation of upper reaches (dotted line) pattern.Utilizing the method according to this invention, is the Capto of 85 μ m with the agarose particle diameter TMThe bed body of Q anion exchange resin loads chromatographic column.Chromatographic column has the volume of 10.8L, the bed height of the diameter of 263mm and 200mm.Then (packed bed volume 1%) acetone monitored the absorbance of 280nm as movement elution from chromatographic column as probe material and water.Can find out from following table 1, use the medium-acetone of 85 μ m, be all to have observed splendid column efficiency at dirty (solid line) or in the pattern of upper reaches (dotted line).
Table 1
Observation The acceptable value
The number of plates/rice (N/m) 4430 ＞3700 (for 85 μ m)
The plate height (h) that reduces 2.5 ＜3.0
Peak asymmetry (Af) 1.14 0.8-1.8
The chromatogram of data source in the table 1 in Fig. 6, as described below.
As shown in Figure 7, as the tolerance of column efficiency, at the chromatographic peak width w of elution chromatographic peak At The Height of half hHelp under the plate height that determine to reduce.This process is approximate correct for the chromatographic peak with gaussian shape.In actual applications, the elution chromatographic peak often can depart from desirable gaussian shape also by so-called dissymmetry factor A fDescribe the offset nature of chromatographic peak, wherein " front the prolonging " among the RTD passes through A fA is then passed through in＜1 expression " taking off tail " f＞1 expression.The general acceptable standard that is used for dissymmetry factor is 0.8＜A f＜1.5-1.8 depends on the type of interpolation.
h = HETP d P = L d P 1 5.54 ( w h V R ) 2
A f=b/a (referring to Fig. 7)
A f: dissymmetry factor
d P: particle diameter
H: the plate height of reduction
HETP: the height that equates with theoretical tray
L: bed height, packed bed
u s: the superficial velocity of packed bed
V R: retention volume
w h: the chromatographic peak width at 50% place of maximum chromatographic peak height

Claims (9)

1. method that is used for loading with the bed of particulate medium body of target bed height disposable axial-flow type chromatographic column,
Described disposable chromatographic column comprises:
The housing that comprises long and narrow tubular sidewall;
By relative, axially spaced the first terminal units and the second terminal units that described sidewall separates, wherein at least one described unit can move axially with respect to another described unit by drive unit;
Be used for described the first terminal units is relied on the fixing pull bar with head of described the second terminal units;
Near the first filter of described first module with near the second filter of described second unit, they define be used to the sealing bed body space that holds the bed of particulate medium body with sidewall and wherein the first filter and/or relatively moving of the second filter can change a height;
Described the first terminal units comprises be used to the first valve gear that utilizes described granule medium packed bed body space; And be used for adding liquid or from the bed body space, removing the first port of liquid to the bed body space;
The second terminal units comprises for adding liquid to the bed body space or remove the second port of liquid from the bed body space;
Described method comprises:
I. the axial spacing between described the first filter and the second filter is adjusted to the distance greater than target bed height;
Ii. the suspension of granule medium is introduced in the bed body space so that the bed body of granule medium to be provided therein by the first valve gear;
Iii. by the bed body that move axially compression described granule medium of described drive unit by the first terminal filter and/or the second terminal filter to form target bed height, described drive unit does not become one with chromatographic column and is connected to chromatographic column from the outside;
Iv. make described the first terminal units rely on described the second terminal units by O type ring and the described pull bar with head fixing to form the fluid tight envelope; And
V. discharge described chromatographic column from described drive unit.
2. the method for claim 1, wherein said drive unit is to choose from the group that is made of actuator, forcing press and framework.
3. such as the described method of any one in the above-mentioned claim, wherein granule medium is the chromatographic media of selecting from the group that is made of Ion Exchange Medium, inverted medium, volume exclusion medium and affinity media.
4. such as the described method of any one among the claim 1-3, wherein the first valve gear is check valve.
5. such as the described method of any one among the claim 1-3, wherein step I i) be included in addition when introducing the suspension of granule medium in the bed body space by the first valve gear and from the bed body space, remove the step of too much liquid to form therein thus the settled bed of granule medium.
6. system that is used for the bed of particulate medium body filling axial-flow type chromatographic column of target bed height, described system comprises:
(i) chromatographic column comprises:
The housing that comprises long and narrow tubular sidewall;
By relative, axially spaced the first terminal units and the second terminal units that described sidewall separates, wherein at least one described unit can move axially with respect to another described unit by drive unit;
Pull bar with head is used for by O type ring and the described pull bar with head described the first terminal units being relied on described the second terminal units fixing to form the fluid tight envelope;
Near the first filter of described the first terminal units with near the second filter of described the second terminal units, they define be used to the sealing bed body space that holds the bed of particulate medium body with sidewall and wherein the first filter and/or relatively moving of the second filter can change a height;
The first terminal units comprises be used to the first valve gear that utilizes described granule medium packed bed body space; And be used for adding liquid or from the bed body space, removing the first port of liquid to the bed body space;
The second terminal units comprises for adding liquid to the bed body space or remove the second port of liquid from the bed body space;
(ii) drive unit;
It is characterized in that described drive unit does not become one with chromatographic column and is connected to chromatographic column from the outside, and wherein said drive unit can discharge from described chromatographic column.
7. system as claimed in claim 6, wherein said drive unit is to choose from the group that is made of framework, forcing press and actuator.
8. such as claim 6 or 7 described systems, wherein the first valve gear is check valve.
9. such as claim 6 or 7 described systems, wherein chromatographic column is disposable chromatographic column.
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WO2008110291A1 (en) 2008-09-18
EP2121157A1 (en) 2009-11-25

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